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(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide (example 261, step G) was transferred as a solution in anhydrous benzene to a pre-weighed, oven-dried 50 mL round bottom flask and stripped to dryness. Azeotropic distillation of benzene/water was performed twice more, and the residue was dried under high vacuum for 2 h, after which it weighed 550 mg. An oven-dried stir bar was added to the flask. The vessel was sealed and purged with nitrogen and then anhydrous dichloromethane (23 mL) was added, followed by triethylamine (1.3 mL, 9.33 mmol). The resulting stirred solution was cooled to 0° C. Methanesulfonyl chloride (0.270 mL, 3.49 mmol) was added dropwise by microsyringe. After 1 h, the reaction was quenched by addition of HCl (1.2M, 12 mL) and diluted in ethyl acetate. The organic layer was washed with 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat. aq. NaCl solution. After drying over magnesium sulfate and concentration in vacuo an intermediate was obtained as an off-white foam (0.64 g,). 1,8-Bis(dimethylamino)naphthalene, 314 mg, 1.465 mmol) and water (0.104 mL, 5.75 mmol) were added to the intermediate, followed by dioxane (23 mL). The mixture was heated under nitrogen at 110° C. overnight. After cooling, the mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution. The aqueous phase was back-extracted with ethyl acetate. The combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with ethyl acetate in hexanes. Chromatography fractions containing predominantly the desired product were combined. The product was re-purified by chromatography on a 40 g silica column, eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give the title compound.

1. customoven-dried 50 mL round bottom flask
2. distillationAzeotropic distillation of benzene/water
3. customthe residue was dried under high vacuum for 2 h
4. additionwas added to the flask
5. customThe vessel was sealed
6. custompurged with nitrogen
7. additionanhydrous dichloromethane (23 mL) was added
8. stirringThe resulting stirred solution
9. customthe reaction was quenched by addition of HCl (1.2M, 12 mL)
10. additiondiluted in ethyl acetate
11. washThe organic layer was washed with 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat. aq. NaCl solution
12. dry with materialAfter drying over magnesium sulfate and concentration in vacuo an intermediate
13. customwas obtained as an off-white foam (0.64 g,)
14. temperatureThe mixture was heated under nitrogen at 110° C. overnight
15. temperatureAfter cooling
16. washwashed with saturated ammonium chloride solution
17. extractionThe aqueous phase was back-extracted with ethyl acetate
18. washThe combined organic layers were washed with sat. aq. NaCl solution
19. dry with materialdried over sodium sulfate
20. filtrationfiltered
21. concentrationconcentrated in vacuo
22. customThe residue was purified by chromatography on silica
23. washeluting with ethyl acetate in hexanes
24. additionChromatography fractions containing predominantly the desired product
25. customThe product was re-purified by chromatography on a 40 g silica column
26. washeluting with a gradient of 0 to 50% ethyl acetate in hexanes